Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum

Jane X. Kelly, Martin J. Smilkstein, Roland A. Cooper, Kristin D. Lane, Robert A. Johnson, Aaron Janowsky, Rozalia A. Dodean, David J. Hinrichs, Rolf Winter, Michael Riscoe

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.

Original languageEnglish (US)
Pages (from-to)4133-4140
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume51
Issue number11
DOIs
StatePublished - Nov 2007

Fingerprint

Acridones
Chloroquine
Plasmodium falciparum
Parasites
Quinine
Nitrogen
Chlorpheniramine
Desipramine
Biogenic Amines
Falciparum Malaria
Imipramine
Antimalarials
Verapamil
Amines
Neurotransmitter Agents
Carbon
Amino Acids
Mutation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum. / Kelly, Jane X.; Smilkstein, Martin J.; Cooper, Roland A.; Lane, Kristin D.; Johnson, Robert A.; Janowsky, Aaron; Dodean, Rozalia A.; Hinrichs, David J.; Winter, Rolf; Riscoe, Michael.

In: Antimicrobial Agents and Chemotherapy, Vol. 51, No. 11, 11.2007, p. 4133-4140.

Research output: Contribution to journalArticle

Kelly, JX, Smilkstein, MJ, Cooper, RA, Lane, KD, Johnson, RA, Janowsky, A, Dodean, RA, Hinrichs, DJ, Winter, R & Riscoe, M 2007, 'Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum', Antimicrobial Agents and Chemotherapy, vol. 51, no. 11, pp. 4133-4140. https://doi.org/10.1128/AAC.00669-07
Kelly, Jane X. ; Smilkstein, Martin J. ; Cooper, Roland A. ; Lane, Kristin D. ; Johnson, Robert A. ; Janowsky, Aaron ; Dodean, Rozalia A. ; Hinrichs, David J. ; Winter, Rolf ; Riscoe, Michael. / Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum. In: Antimicrobial Agents and Chemotherapy. 2007 ; Vol. 51, No. 11. pp. 4133-4140.
@article{6674872e1cbb4cee8e73fe9b2b6b32ea,
title = "Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum",
abstract = "A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.",
author = "Kelly, {Jane X.} and Smilkstein, {Martin J.} and Cooper, {Roland A.} and Lane, {Kristin D.} and Johnson, {Robert A.} and Aaron Janowsky and Dodean, {Rozalia A.} and Hinrichs, {David J.} and Rolf Winter and Michael Riscoe",
year = "2007",
month = "11",
doi = "10.1128/AAC.00669-07",
language = "English (US)",
volume = "51",
pages = "4133--4140",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "11",

}

TY - JOUR

T1 - Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum

AU - Kelly, Jane X.

AU - Smilkstein, Martin J.

AU - Cooper, Roland A.

AU - Lane, Kristin D.

AU - Johnson, Robert A.

AU - Janowsky, Aaron

AU - Dodean, Rozalia A.

AU - Hinrichs, David J.

AU - Winter, Rolf

AU - Riscoe, Michael

PY - 2007/11

Y1 - 2007/11

N2 - A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.

AB - A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.

UR - http://www.scopus.com/inward/record.url?scp=35848940753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35848940753&partnerID=8YFLogxK

U2 - 10.1128/AAC.00669-07

DO - 10.1128/AAC.00669-07

M3 - Article

C2 - 17846138

AN - SCOPUS:35848940753

VL - 51

SP - 4133

EP - 4140

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 11

ER -